Poxel Announces Initiation of Part 2 of Phase 1a Study for PXL065, which is being Developed for the Treatment of NASH

PXL065 data to date suggest the potential for a favorable profile
for the treatment of NASH

LYON, France--(BUSINESS WIRE)--
POXEL
SA (Euronext: POXEL - FR0012432516), a biopharmaceutical company
focused on the development of innovative treatments for metabolic
disorders, including type 2 diabetes and non-alcoholic steatohepatitis
(NASH), today announced that Part 2 of the Phase 1a study for PXL065, a
deuterium-stabilized R-stereoisomer of pioglitazone, has been initiated.
This second part of the Phase 1a study will enroll six healthy subjects
per group, with a primary objective to assess safety and tolerability
and a secondary objective to assess dose proportionality. This Phase 1a
trial, which was discussed with the U.S. Food and Drug Administration
(FDA) in a pre-Investigational New Drug Application (IND) meeting, was
designed to include two single oral doses and potentially up to three
additional doses of PXL065.

In Part 1 of the Phase 1a study, which was presented during the 2018
American Association for the Study of Liver Diseases (AASLD) meeting,
twelve healthy subjects received a single oral dose of 22.5 mg PXL065 or
45 mg Actos®*. In this study, PXL065 was shown to be safe and
well-tolerated with no adverse events. Based on the pharmacokinetic (PK)
results, modeling predicts that a 15 mg dose of PXL065 may provide a
similar exposure of R-pioglitazone as a 45 mg dose of the parent drug,
pioglitazone (Actos), which suggests it should show similar efficacy
with an improved safety profile, including reduced weight gain and fluid
retention.

“Nonalcoholic fatty liver disease (NAFLD) is reaching epidemic
proportions worldwide and is the most common chronic liver condition in
obese patients with prediabetes or type 2 diabetes mellitus,” said
Kenneth Cusi, MD, Chief of the Division of Endocrinology, Diabetes &
Metabolism in the Department of Medicine at the University of
Florida. “Because the mechanism of action for PXL065 is known to target
mitochondrial pyruvate carrier (MPC) inhibition, PXL065 is expected to
have beneficial effects on insulin resistance and inflammation, which
are key components for treating steatohepatitis in patients with NASH.”

“Shortly after signing the acquisition agreement with DeuteRx for
PXL065, the IND for PXL065 was transferred to Poxel, and we
subsequentially initiated Part 2 of the Phase 1a study. Data generated
from this latest study of PXL065, including the PK results and modeling
work based on the highest approved dose of pioglitazone, should enable
us to establish optimal doses for the next phase of development,” said
Thomas Kuhn, CEO of Poxel.

“The underlying pathophysiological mechanisms that contribute to the
development and progression of NAFLD and NASH are highly complex and
support the need for the development of novel therapies acting on
different targets. We believe that addressing a variety of relevant
pathways, such as mitochondrial pyruvate carrier (MPC) inhibition with
PXL065 and direct adenosine monophosphate-activated protein kinase
(AMPK) activation with PXL770, could yield greater success in the
treatment of NASH,” continued Thomas Kuhn. “We look forward to advancing
both of our programs for the treatment of NASH into proof-of-concept
studies in 2019.”

Pioglitazone, a drug approved for the treatment of type 2 diabetes has
demonstrated therapeutic efficacy for NASH, even in patients with
advanced fibrosis. Pioglitazone is the only drug recommended for
biopsy-proven NASH patients by the Practice Guidelines published by the
American Association for the Study of Liver Diseases (AASLD) and the
European Association for the Study of the Liver (EASL).1
However, its therapeutic use and potential have been limited due to the
PPARγ-related side effects of weight gain, bone fractures and fluid
retention. PXL065, a novel patent-protected drug candidate, offers an
expected new approach for the treatment of NASH and has the potential to
preserve the pharmacological benefits of pioglitazone required for the
treatment of NASH, such as a reduction of hepatic steatosis,
inflammation, ballooning and fibrosis and could reduce PPARγ agonism and
the associated side effects that are thought to be related to
S-pioglitazone.

About NASHNon-alcoholic steatohepatitis (NASH) is a
metabolic disease with no clear disease origin that is quickly becoming
a worldwide epidemic. It is characterized by the accumulation of fat in
the liver causing inflammation and fibrosis. The disease can be silent
for a long period of time, but once it accelerates, severe damage and
liver cirrhosis can occur, which can significantly impact liver function
or can even result in liver failure or liver cancer. Typical risk
factors for NASH include obesity, elevated levels of blood lipids (such
as cholesterol and triglycerides) and diabetes. Currently no curative or
specific therapies are available.

About PXL065PXL065, formerly DRX-065, is
deuterium-stabilized R-pioglitazone. Pioglitazone is the most
extensively studied drug for NASH and has demonstrated “resolution of
NASH without worsening of fibrosis” in a Phase 4 trial2. Pioglitazone
is the only drug recommended for biopsy-proven NASH patients by the
Practice Guidelines published by the American Association for the Study
of Liver Diseases (AASLD) and the European Association for the Study of
the Liver (EASL).1 Pioglitazone’s use for NASH, however,
has been limited due to the PPARγ-related side effects, which include
weight gain, bone fractures and fluid retention.

Pioglitazone is a 1:1 mixture of two mirror-image compounds
(stereoisomers) that interconvert in vivo. Using deuterium,
DeuteRx stabilized each stereoisomer and characterized their
dramatically different pharmacological properties. In in vitro studies,
PXL065 has been shown to target MPC as an inhibitor. In preclinical
models, PXL065 exhibits the anti-inflammatory activity and NASH efficacy
associated with pioglitazone with little or no weight gain or fluid
retention, side effects which are associated with the S-stereoisomer.
Based upon preclinical and Phase 1 results to date, PXL065 is expected
to exhibit a better therapeutic profile than pioglitazone for NASH.

About PXL770PXL770 is a first-in-class direct adenosine
monophosphate-activated protein kinase (AMPK) activator. AMPK is a
central regulator of multiple metabolic pathways leading to the control
of lipid metabolism, glucose homeostasis and inflammation. Based on its
central metabolic role, targeting AMPK offers the opportunity to pursue
a wide range of indications to treat chronic metabolic diseases,
including diseases that affect the liver, such as non-alcoholic
steatohepatitis (NASH)3.

About Poxel SAPoxel uses its development expertise in
metabolism to advance a pipeline of drug candidates focused on the
treatment of metabolic disorders, including type 2 diabetes and
non-alcoholic steatohepatitis (NASH). We have successfully completed the
Phase 2 clinical program for our first-in-class lead product, Imeglimin,
which targets mitochondrial dysfunction, in the U.S., Europe and Japan.
Together, with our partner Sumitomo Dainippon Pharma, we are conducting
the Phase 3 Trials of Imeglimin for Efficacy and Safety (TIMES) program
for the treatment of type 2 diabetes in Japan. Our partner Roivant
Sciences is responsible for Imeglimin’s development and
commercialization in countries outside of Poxel’s partnership with
Sumitomo Dainippon Pharma, including the U.S. and Europe. PXL770, a
first in class direct adenosine monophosphate-activated protein kinase
(AMPK) activator, is advancing into a Phase 2a proof-of-concept program
for the treatment of NASH. PXL770 could also have the potential to treat
additional metabolic diseases. PXL065 (deuterium-stabilized
R-pioglitazone), a mitochondrial pyruvate carrier (MPC) inhibitor, is in
Phase 1 and being developed for the treatment of NASH. Poxel also has
additional earlier-stage programs, including deuterated drug candidates
for metabolic, specialty and rare diseases. We intend to generate
further growth through strategic partnerships and pipeline development.
(Euronext: POXEL, www.poxelpharma.com)

*Actos is the branded version of pioglitazone and a registered trademark
of Takeda Chemical Industries, Ltd.